1. Technical Field of the Invention
The present invention relates to the administration of at least one double-stranded RNA oligonucleotide (dsRNA) via topical application and to compositions for topical administration which comprise at least one encapsulated double-stranded RNA oligonucleotide formulated into a physiologically acceptable medium therefor.
2. Description of Background and/or Related and/or Prior Art
A large number of substances are administered topically for compensating for or preventing certain aesthetic impairments or certain disorders of the skin or its appendages. Of these substances, those which exhibit true biological specificity are more particularly desired.
Thus, the greater the extent to which the substances exhibit a specific activity, such as a specific biological activity, the less likely it is that they will induce undesirable side effects. For example, preference will be given to formulating a substance whose action is targeted on an enzyme such as tyrosinase into a composition which seeks to clear the complexion or prevent undesirable pigmentation. Mention may also be made, by way of example, of formulating a substance which acts specifically on certain metalloproteinases or elastases into a composition for preventing aging.
To date, this problem of specificity has been resolved by administering native DNA or RNA oligonucleotides or antisense DNA. However, such application has its limitations.
Thus, including DNA, non-specific RNA or antisense DNA oligonucleotides (such as those described, for example, in WO 01/58918) in topical formulations has not enabled any desirable efficacy to be obtained. In particular, RNases on the surface of the skin degrade native RNA and it is not possible for the quantities reaching the target mRNAs to be sufficient to obtain the desired effect. Another limitation to administering single-stranded oligonucleotides such as those mentioned above is the risk of the oligonucleotide possibly undergoing secondary refolding (or secondary re-pairing). For this reason, administering single-stranded oligonucleotides (such as antisense DNA oligonucleotides) in vivo is frequently ineffective. Furthermore, the stability of the effects produced by single-stranded oligonucleotides in vivo is short because of the oligonucleotides being broken down rapidly intracellularly and having a short extracellular half-life in vivo (Khan A et al., J. Drug Target, 2000, 8, 319-334).
Thus a need continues to exist for a composition which resolves both the difficulties of administering active compounds in a targeted manner and the problem of specificity and which is suitable for topical application.
Double-stranded RNA oligonucleotides, also termed dsRNAs, have long been known to be present in plants and eukaryotic organisms (Haines D. S. et al., J. Cell Biochem., 1991; 46:9-20); their role is to inhibit the expression of a specific gene (Fire A., Trends in Genetic, 1999; 15:358-363).
Using dsRNA for therapeutic purposes has been described in WO 01/36646, which proposes a method for inhibiting genes which are involved in diseases, in particular cancers. The examples of implementing this method propose inhibiting the expression of a gene in undifferentiated cells, such as embryonic cells, or oocytes, by intracellularly injecting dsRNA which is targeted at the gene to be inhibited. The objective is to obtain a systemic effect. The modes of administration envisaged concern general administrations.
Contrary to the pharmaceutical compositions which are proposed in this publication, a topical formulation should reach a specific differentiated cell while at the same time only acting at the superficial level, that is to say at the level of the skin or its appendages (dermis, epidermis and keratinized appendages), or even only at the surface of the skin by targeting the eukaryotic microorganisms which cover it. It is also possible to search for an effect on a specific skin cell type, such as a fibroblast, a melanocyte, a keratinocyte, a Langerhans cell or an endothelial cell which is involved in aesthetic impairments or particular dermatological disorders.